Bob Kronemyer

Eugenol, the chief phenolic component of 

 essential oil, is a novel therapeutic agent for the inhibition of 

species infection, according to a review published in 

Eugenol could assist in the clinical management of candidiasis, especially localized forms like vulvovaginal and oral candidiasis, due to its fungicidal activity and inhibitory effect on germ tube formation.

The compound may also provide a synergistic effect in combination with fluconazole.

The review is 1 of 3 articles in the publication on the research topic discovering novel microbe-modulating agents from natural resources.

The authors cited high occurrence and mortality rates stemming from candidiasis, along with costly medical care, as reasons for new treatments.

Eugenol has been used to inhibit growth and different virulence factors of 

, including strains with decreased susceptibility to antifungals; foremost, fluconazole.

“The results showed that this compound could bind to 

 membrane and decrease ergosterol biosynthesis, consequently leading to cell wall and membrane damage,” wrote the authors.

Eugenol not only reduced germ tube formation, thus decreasing nutrient absorption from host tissues, but increased the levels of lipid peroxidation and reactive oxygen species; hence, inducing oxidative stress and causing high permeability in the fungal cell membrane.

 cells’ adhesion capacity. The compound also inhibited the formation of biofilms and eliminated 

The authors noted that by disrupting fungal cell integrity, eugenol might boost the entry of the antifungal drugs into the 

Overall, eugenol could be used in the clinical management of various presentations of candidiasis, particularly mucocutaneous presentations like oral and vulvovaginal infections.

Because of the potent anti-biofilm capacity of eugenol against 

, coating medical implant devices with this compound may be practical in preventing implant-associated 

The combined use of eugenol with various antifungals, especially fluconazole, might also be helpful in treating infections caused by drug-resistant 

A recently published study in the journal 

 found that eugenol could increase the efficacy of fluconazole against clinical 

 For the study, the essential oil and methanolic and ethanolic extracts obtained from the aerial parts of 

 Mill. (Ecuador) were chemically characterized via gas-chromatography coupled to mass spectrometry detector (GC-MS) andhigh-performance liquid chromatography coupled to diode array-mass spectrometry detectors (HPLC-DAD-MS), then studied for their in vitro biological activity.

Essential oil and eugenol demonstrated notable activity against 

 and a moderate effect against clinical 

 strains, along with potential synergism with fluconazole.

Studies on the genotoxicity and cytotoxicity of eugenol arecontroversial and limited. A dose of 2.5 mg/kg body weight of eugenol is considered safe by the Food and Agriculture Organization of the United Nations, but high concentrations of the compound could be harmful and pro-oxidative.

 and animal studies, toxicology studies, clinical trials and molecular analysis to improve formulations and develop novel antifungal agents based on eugenol.

This article originally appeared on Contemporary OB/GYN.

1. Didehdar M, Chegini Z, Shariati A. Eugenol: a novel therapeutic agent for the inhibition of 

. Published online August 9, 2022. doi:org/10.3389/fphar.2022.872127

2. Tacchini M, Echeverria Guevara MP, Grandini A, et al. 

 mill. from Amazonian Ecuador: chemical composition and biological activities of extracts and their main constituents (eugenol and rosmarinic acid). 

 26 (1), 84. doi:10.3390/molecules26010084

Articles

Using Eugenol to Treat Candida Species Infection

Myovant Sciences and Pfizer recently announced positive results of the phase 3 SPIRIT 1 and SPIRIT 2 studies evaluating the investigational combination therapy of relugolix, estradiol and norethindrone acetate (Myfembree; Myovant and Pfizer) for moderate to severe endometriosis-associated pain.

In both studies, 75% of women using the once daily relugolix combination therapy experienced a significant reduction in dysmenorrhea, compared to 27% and 30% of women in the placebo groups at Week 24, respectively (both 

 < 0.0001). Relugolix combination therapy also significantly reduced non-menstrual pelvic pain in 59% and 66% of women, compared to 40% and 43% in the placebo groups (

In SPIRIT 1 and 2, the relugolix combination therapy group also showed reductions in dyspareunia and opioid use compared to the placebo groups. Additionally, more women undergoing relugolix combination therapy were opioid free at Week 24 compared with placebo (86% and 82% vs 76% and 66%, respectively).

The most frequently reported adverse events by women in both the relugolix combination therapy and placebo groups included headaches, nasopharyngitis, and hot flashes.

Currently, the relugolix combination tablet (relugolix 40 mg, estradiol 1.0 mg, and norethindrone acetate 0.5 mg) is available in the United States as Myfembree for the management of uterine fibroid-related heavy menstrual bleeding in premenopausal women.

“The data [from SPIRIT 1 and 2] underscore the value relugolix combination therapy may provide as a potential new treatment option for women with endometriosis-associated pain,” said Juan Camilo Arjona Ferreira, MD, chief medical officer of Myovant Sciences.

According to the studies’ authors, “this oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment.”

Data from SPIRIT 1, SPIRIT 2, and an open-label extension study were included in a supplemental New Drug Application for the relugolix combination tablet for the management of moderate to severe endometriosis pain with a target Prescription Drug User Fee Act of August 6, 2022.

Myovant Sciences and Pfizer Announce Publication in The Lancet of Phase 3 SPIRIT 1 and SPIRIT 2 Studies of Once-Daily Relugolix Combination Therapy in Women With Endometriosis-Associated Pain | Myovant Sciences Ltd. Myovant Sciences Ltd. Published 2022. Accessed June 22, 2022. 

https://investors.myovant.com/news-releases/news-release-details/myovant-sciences-and-pfizer-announce-publication-lancet-phase-3

Giudice LC, As-Sanie S, Arjona Ferreira JC, et al. Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2). 

. 2022;399(10343):2267-2279. doi:10.1016/s0140-6736(22)00622-5

Results suggest the potential of this oral therapy to address the unmet clinical need for long-term medical treatment for endometriosis.

Relugolix Produced Positive Phase 3 Results for Endometriosis Pain

The authors, who conducted a systematic literature search of PubMed, PsycINFO and Embase, found some evidence of altered development in specific outcomes, but the literature is minimal.

Short-term consequences of prenatal exposure to benzodiazepines include adverse birth outcomes such as preterm birth, floppy baby syndrome, lower Apgar scores and neonatal withdrawal syndrome. But any long-term consequences of prenatal exposure to the drugs is uncertain.

The 13 cohort studies comprising the review recruited participants between 1958 to 2014, for which the length of follow-up varied greatly.

Four of the included studies were from Norway, based on the Norwegian Mother, Father and Child Cohort Study (MoBa). Of the remaining nine studies, two were from Sweden, two from the United States, and one each from Denmark, the Czech Republic, the Netherlands, France and Canada.

The 13 studies reported one or more of the following outcomes: internalizing and externalizing problems, language, hearing and communication skills, neurological outcomes and motor function, behavioral and emotional problems, social skills, intellect and academic achievements, psychiatric diagnoses and overall development.

Some studies gleaned information from children's teachers and parents, and one study relied on teachers only. The four studies from Norway used validated questionnaires filled out by parents.

Direct examination of the children by a professional healthcare worker was employed in two studies and databases were used in two other studies.

The review found that prenatal exposure to benzodiazepines was associated with four developmental outcomes indicating an impaired long-term-development of the offspring:internalizing problems, impaired gross motor skills, lower academic achievements and increased attention-deficit/hyperactivity disorder (ADHD) traits.

“However, results were contradicting, and it cannot be ruled out, that findings might be due to bias,” wrote the authors. For example, self-report and interviewing of the mothers were widely used, for which underreporting of benzodiazepines use during pregnancy could occur.

 in 2019, found a link between prenatal exposure to benzodiazepines and the studied outcome in children of mothers suffering from depression/anxiety, but not in children of mothers suffering from other indications for the drugs.

 This finding underscores the role of an underlying maternal disorder.

It remains uncertain if review results are of clinical relevance and whether developmental problems persist in later childhood, according to the authors.

In addition, many studies lacked power to perform adjusted analyses and robust results.

Studies were also limited to those written in Danish or English, which could have excluded relevant literature written in other languages.

Moreover, long-term childhood development requires a long follow-up period, for which the majority of studies did not have. Still, several of the studies made analyses to account for the lack of longer follow-up, thus increasing the validity of their findings.

The review reveals a clear need for further research on the subject, according to the authors.

1. Jensen AG, Knudsen SS, Bech BH. Prenatal exposure to benzodiazepines and the development of the offspring – a systematic review. 

. Published online February 18, 2022. doi:org/10.1016/j.ntt.2022.107078

2. Lupattelli A, Bandoli G, Handal M, et al. Association of maternal use of benzodiazepines and Z-hypnotics during pregnancy with motor and communication skills and attention-deficit/hyperactivity disorder symptoms in preschoolers. 

. 2019. doi:10.1001/jamanetworkopen.2019.1435

Prenatal use of the psychoactive drug benzodiazepines is not a major risk factor for altered neurodevelopment in early childhood, despite crossing the human blood-placenta barrier.

Examining the Effects of Prenatal Exposure to Benzodiazepines

Ibrexafungerp provides activity against a variety of multidrug-resistant fungi, including 

, according to a review of the pharmacokinetics and pharmacodynamics of the medicine published in the journal 

Ibrexafungerp is a first-in-class triterpenoid antifungal agent in an oral formulation. “Similar to echinocandins, ibrexafungerp inhibits (1→3)-β-d-glucan synthase, a key component of the fungal cell wall, and has both in vitro and in vivo activity against a variety of clinically relevant fungal species, including the yeast 

,” wrote author Matthew William McCarthy, MD, from the Department of Medicine at Weill Cornell Medicine in New York City.

Because the drug retains in vitro activity against both echinocandin-resistant and triazole-resistant strains of pathogenic fungi, it is well positioned to address the mounting challenge of drug-resistant invasive fungal infections.

A single-center, open-label phase I study of healthy subjects that assessed the drug–drug interaction potential between ibrexafungerp and the immunomodulator tacrolimus found that co-administration of the two medicines had no effect on the maximum blood concentrations of tacrolimus.

The study also concluded there was no change in the maximum concentration of tacrolimus in plasma and a 1.4-fold increase in total area under the curve (AUC). This indicates that a dose adjustment for tacrolimus may not be needed when combined with ibrexafungerp, according to McCarthy.

A multicenter, open-label phase II study randomized patients with invasive candidiasis to one of three stepdown therapies: two dosing regimens of oral ibrexafungerp or standard of care following initial echinocandin therapy.

Satisfactory response rates for the study were 86% in the ibrexafungerp 750-mg arm compared to 71% for either ibrexafungerp 500-mg or standard of care. All treatment regimens were also well tolerated.

A population pharmacokinetic analysis of the study concluded that the ibrexafungerp 750-mg regimen leads to target exposure in roughly 85% of the population.

A follow-up phase II, randomized, double-blind, dose-finding study comparing ibrexafungerp to fuconazole for treating VVC found that 1 month after diagnosis, clinical cure rates were higher for ibrexafungerp than for fuconazole: 70% vs. 50%.

The FDA approved ibrexafungerp after two successful randomized, double-blind, placebo-controlled, phase 3 clinical trials.

In one of the two trials, clinical cure, mycological eradication and clinical improvement at day 25 for ibrexafungerp compared to placebo were 51 vs 29%, 50 vs 19% and 64% vs 37%, respectively.

The primary endpoint of the other trial was clinical cure rate, which was defined as the complete resolution of all signs and symptoms at the test-of-cure visit on day 10. Clinical cure, mycological eradication and clinical improvement for ibrexafungerp compared to placebo were 63% vs. 44%, 59% vs. 30% and 72% vs. 55%, respectively.

Ibrexafungerp is currently being investigated for numerous invasive conditions, including fungemia, as either standalone treatment or in combination with other antimicrobial agents.

McCarthy MW. Pharmacokinetics and pharmacodynamics of ibrexafungerp. 

. 2022. 22:9–13. doi:org/10.1007/s40268-021-00376-x

Wring S, Murphy G, Atiee G,et al. Clinical pharmacokinetics and drug–drug interaction potential for coadministered SCY-078, an oral fungicidal glucan synthase inhibitor, and tacrolimus. 

Spec A, Pullman J, Thompson GR, et al. MSG-10: a phase 2 study of oral ibrexafungerp (SCY-078) following initial echinocandin therapy in non-neutropenic patients with invasive candidiasis. 

Azie N, Angulo D, Dehn B, et al. Oral ibrexafungerp: an investigational agent for the treatment of vulvovaginal candidiasis. 

Jallow S, Govender NP. Ibrexafungerp: a first-in-class oral triterpenoid glucan synthase inhibitor. 

Seiler GT, Ostrosky-Zeichner L. Investigational agents for the treatment of resistant yeasts and molds. 

In June 2021, ibrexafungerp (Brexafemme; Scynexis) became the first drug approved by the U.S. Food and Drug Administration (FDA) in a novel antifungal class in more than 20 years and is now available to treat vulvovaginal candidiasis (VVC).

Treating Vulvovaginal Candidiasis with Ibrexafungerp

Access to immediate postpartum long-acting reversible contraception can improve outcomes. 

 indicates that policies that increase access to immediate postpartum long-acting reversible contraception (LARC) improve birth outcomes.

“The relationship between postpartum contraception, birth intervals and infant outcomes is often assumed, and underscores a lot of family planning research and policy,” said principal investigator Maria Steenland, SD, a research assistant professor at the Population Studies and Training Center, Brown University, Providence, Rhode Island. “However, very little research has investigated the relationship between postpartum family planning and infant outcomes.”

The study focused on South Carolina’s Medicaid program, which in 2012, began to reimburse hospitals for immediate postpartum LARC and separate from the global maternity payment.

A sample of 186,953 Medicaid-paid births in the state between January 2009 and December 2015 were assessed—81,110 births from 2009 to 2011 (prior to policy change); 105,843 births from 2012 to 2015 (post-policy change); and 46,414 births in exposure hospitals (birth in an implementing-policy hospital between 2012 and 2015).

The policy was linked to an absolute 5.6% increase in the overall probability of receiving an immediate postpartum LARC.

Most pronounced was the effect on non-Hispanic Black women, among whom the increase in immediate postpartum LARC was 3.54 percentage points greater than for non-Hispanic White women (

The policy was also associated with a 0.4% decrease in the probability of subsequent preterm birth and a 0.3% reduction in the likelihood of subsequent low birth weight.

However, there were no significant differences in policy and preterm birth or low birth weight between non-Hispanic Black and non-Hispanic White individuals.

Conversely, the policy was linked to a 0.6% decrease in the probability of short-interval birth and a 27-day increase in days to next birth among non-Hispanic Black individuals.

The policy was also associated with a significant decrease in the probability of a subsequent birth within 4 years. “But confidence in this finding is somewhat attenuated by nonparallel trends for this outcome before the policy change,” Steenland told 

The main results of the study do not surprise Steenland because “there are several ways that immediate postpartum LARC could reduce preterm births and low birth weight, such as fewer births overall, fewer short interval births and fewer unintended births.”

The findings of the study are more relevant to policy than to clinical decision-making, according to Steenland, because outcomes of the study were measured among all people who gave birth in a given time period and may be driven by a decrease in the percentage of people who have another birth.

“Future studies examining the effect of waiting 24 months compared to 12 months on infant health, for example, could inform individual decision-making about birth spacing,” she said.

Steenland would like to see policy efforts that expand access to all methods of contraception, including after childbirth hospitalizations though Medicaid expansion, in remaining non-expansion states; maintain federal funding for family planning through Title X; and remove state-level policies that restrict funding to safety-net family planning providers like Planned Parenthood.

“It is also important that immediate postpartum LARC policy implementation be patient-centered and antiracist, so that contraceptive autonomy is not compromised,” said Steenland, who noted that large racial disparities in infant outcomes continue in South Carolina and nationwide.

This article originally appeared on Contemporary Ob/Gyn.

Steenland MW, Pace LE, Cohen JL. Association of Medicaid reimbursement for immediate postpartum long-acting reversible contraception with infant birth outcomes. 

. Published online January 10, 2022. doi:10.1001/jamapediatrics.2021.5688

Immediate Postpartum LARC Access Improves Birth Outcomes

About 1 in 5 girls with pediatric type 2 diabetes (T2D) also has polycystic ovary syndrome (PCOS), according to a systematic review and meta-analysis in JAMA Network Open.

“T2D in youth is on the rise. It is an aggressive disease with high treatment failure rates,” said senior author M. Constantine Samaan, MD, MSc, an associate professor of pediatrics at McMaster University in Hamilton, Ontario, Canada. “While we know that PCOS occurs in girls with T2D, the scale of this condition is not fully known. Our group focused on understanding the global prevalence of PCOS in girls with T2D.”

For the review, the authors devised a search strategy that examined information across several literature databases.

The analysis comprised 470 girls from 6 studies, and the prevalence of PCOS in girls with T2D was 19.58%.

Because heterogeneity among studies was moderate to high, the authors conducted another analysis in which only the studies that reported the exact diagnostic criteria of PCOS were included. This second analysis showed that the prevalence was 24.04%.

“The biggest surprise was that we discovered that girls with T2D were at least twice as likely to have PCOS than those without diabetes,” Samaan told 

In the literature, up to 1 in 9 girls with T2D are diagnosed with PCOS, “but there is a wide range in those figures,” Samaan said. “Our calculation of nearly one in five may in reality be even higher.”

The link between PCOS and T2D in adults is bidirectional, with insulin resistance playing a pivotal role in the pathogenesis of PCOS. “Studies have shown that girls with PCOS have decreased insulin sensitivity and compensatory hyperinsulinemia, which is associated with T2D risk,” Samaan said.

Another potential mechanism that may lead to both insulin resistance and hyperandrogenism is lipotoxicity.

“One of the important findings of the study was that there were no data to determine the association of obesity and race with PCOS risk, which are important associations of T2D,” said Samaan, a staff physician in pediatric endocrinology at McMaster Children's Hospital in Hamilton. “Obesity is considered the main driver of T2D, but some girls with PCOS are neither overweight nor obese. Also, non-Caucasians have a higher risk for T2D than Caucasians.”

But Samaan said the results of the meta-analysis should be cautiously considered because it included studies of larger numbers of girls that did not report the criteria used to diagnose PCOS, “which is a challenge during adolescence.”

Considering that T2D has other associated morbidities, such as fatty liver disease, sleep apnea, abnormal lipids, and hypertension, “the burden of care on these girls is significant,” he said. “Health care providers must be aware of the scale of PCOS in T2D patients, and ask patients about their periods, but also make patients aware of the risk of PCOS with T2D.”

Samaan also noted that it is critical that active screening for PCOS in girls with T2D be initiated at diabetes diagnosis and follows international evidence-based guidelines for diagnosing PCOS in adolescents, as there are treatments that can be offered to manage PCOS.

“In addition, further studies need to estimate some of the drivers of PCOS in these girls, and more molecular studies are required to determine the exact mechanisms of PCOS in T2D,” he said.

Cioana M, Deng J, Nadarajah A, et al. Prevalence of polycystic ovary syndrome in patients with pediatric type 2 diabetes: a systematic review and meta-analysis. 

. Published online February 15, 2022. doi:10.1001/jamanetworkopen.2021.47454

PCOS prevalence in girls with type 2 diabetes was almost 20%.